Nonalcoholic steatohepatitis (NASH) involves the development of histologic changes in the liver that are comparable to those induced by excessive alcohol intake but in the absence of alcohol abuse. Macrovesicular and/or microvesicular steatosis, lobular and portal inflammation, and occasionally Mallory bodies with fibrosis and cirrhosis characterize NASH. NASH is also commonly associated with hyperlipidemia, obesity, and type II diabetes mellitus. Other clinical conditions characterized by hepatic steatosis and inflammation include excessive fasting, jejunoileal bypass, total parental nutrition, chronic hepatitis C, Wilson's disease, and adverse drug effects such as those from corticosteroids, calcium channel blockers, high dose synthetic estrogens, methotrexate and amiodarone. Thus, the term "nonalcoholic steatohepatitis" can be used to describe those patients who exhibit these biopsy findings, coupled with the absence of (a) significant alcohol consumption, (b) previous surgery for weight loss, (c) history of drug use associated with steatohepatitis, (d) evidence of genetic liver disease or (e) chronic hepatitis C infection. See, J. R. Ludwig et al., Mayo Clin. Proc., 55, 434 (1980) and E. E. Powell et al., Hepatol., 11, 74 (1990).
The pathogenesis of NASH is unknown. A correlation seems to exist between the degree of steatosis and the degree of fibrosis. For example, see I. R. Wanless et al., Hepatology, 12, 1106 (1990). Elevated hepatocellular free fatty acids may cause membrane injury with subsequent inflammation, possible cholestasis, and subcellular organelle dysfunction. Cell death and fibrosis follow persistent inflammation, and cirrhosis occurs if the injury continues. Steatohepatitis is now considered an important cause of end-stage liver disease and may be the cause of an unknown number of cases of clyptogenic cirrhosis. See E. E. Powell et al, cited above. Unfortunately, once cirrhosis is established, the only therapeutic modality available is orthotopic liver transplantation. Thus, effective therapy for nonalcoholic steatohepatitis is clearly needed.